JP2003043041A - Liquid discharge device and apparatus for manufacturing sample carrier - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a liquid discharge device which is suitable for efficiently manufacturing a sample carrier such as a probe carrier or the like for a probe array and which has a simple constitution and to provide an apparatus and a method for manufacturing the sample carrier by using the liquid discharge device. SOLUTION: The liquid discharge device which has a discharge port used to discharge a liquid held inside a flow channel by using energy such as heat or the like, is constituted in such a way that an atmospheric pressure chamber capable of changing atmospheric pressure and the flow channel which makes the atmospheric pressure chamber communicate with the discharge port and which can hold the liquid are installed and that the liquid can be filled from the outside into the flow channel from the discharge port by using a reduced pressure generated in the atmospheric pressure chamber. A spot of a sample is formed on a carrier by using the liquid discharge device, and the sample carrier is manufactured.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention discharges a liquid containing a sample as a component relating to a desired reaction as fine droplets,
The present invention relates to a liquid ejection device useful for manufacturing a sample carrier chip arranged on a carrier as a matrix array of precise spot groups. Specific examples of the main fields of use of this apparatus include an apparatus for producing a reaction chip such as a probe carrier having spots of probes used for DNA analysis, DNA diagnosis and the like.

[0002]

BACKGROUND ART Research is underway to analyze and diagnose DNA that affects diseases caused by gene mutations. DNA
As a method for analyzing the DNA, as shown in FIG. 8, several thousand to tens of thousands of different known DNA fragments (DNA probes) that have already been decoded are usually used on a slide glass or a silicon chip of about 1 to 3 cm square. In a matrix array of several hundred μ
It is effective to use a reaction chip, which is generally called a DNA chip, which is applied at high density without overlapping each other at intervals of m or less.

For example, when a sample obtained by labeling DNA taken out from cells of an organism with a fluorescent dye is dropped onto this DNA chip, the DNA sample becomes a DNA probe on the DNA chip having a sequence complementary thereto. Since it hybridizes, by irradiating the DNA chip with excitation light that excites the fluorescent dye, only the binding part has fluorescence, and by using a photodetector, the DNA probe corresponding to the emission position on the DNA chip. Can be identified and thus the sequence of the DNA sample can be elucidated.

A general method for producing such a DNA chip includes a method of synthesizing and purifying a DNA probe on the chip by using a photolithography technique used in the semiconductor industry, and a method of preliminarily synthesizing a DNA probe on the chip. There is known a method of spotting the chip on the chip and connecting the chip with the chip.

[0005]

[Problems to be Solved by the Invention] When preparing a DNA chip by the above method, it is necessary to prepare sophisticated and large-scale equipment. Therefore, for example, when a researcher wants to immobilize a unique DNA probe on a DNA chip as a carrier, it is not easy to satisfy this requirement. Further, it is known that it is very difficult to purify the DNA probe on the chip by this manufacturing method. Since the detection accuracy of a DNA sample largely depends on the degree of purification of a DNA probe, further improvement is required for this method in producing a high quality DNA chip.

On the other hand, the above manufacturing method is a manufacturing method in which the problems of the above manufacturing method are improved. In this manufacturing method, it is necessary to synthesize a DNA probe in advance, but since the DNA probe can be easily purified before binding to the chip, a high quality DNA probe can be prepared.

However, there are some problems in this manufacturing method.

The first is a method of spotting DNA probes on a chip at high density. In performing DNA analysis, it is often necessary to obtain a very small amount of DNA sample from a subject and obtain as much DNA information as possible from a small amount of sample. Ie DNA
As many chips as possible (usually thousands to tens of thousands) are coated on a chip of about 1 to 3 cm square in a matrix array with high density at intervals of several hundred μm or less. Is required.

The second problem is to apply each DNA probe with good reproducibility, that is, to apply the dot size of each DNA probe uniformly and with reproducibility. For example, when determining the quantification of an analyte, individual DNA
All probe spot diameters should be approximately equal.

The third problem is how to fill the coating means with the synthesized DNA probe. Since there may be tens of thousands of DNA probes, it is necessary that each of a large number of coating means can be easily filled with various DNA probe solutions. That is, in order to apply tens of thousands of types of DNA probes, a reservoir for storing the DNA probe solution corresponding to each DNA probe and a means for ejecting and applying the DNA probe solution from each reservoir (for example, a nozzle, a pin, etc.) ), It becomes necessary to prepare a supply pipe that directly connects the reservoir and the coating means. However, if a coating means that corresponds to various kinds of DNA probes is prepared, the device becomes very large. In order to avoid this, it is effective to fill several kinds of DNA probes into one coating means several times. in this case,
To obtain the reliability of the device and product, after applying a certain DNA probe to the chip, wash the applying means once and
A complicated process of refilling the coating means with the DNA probe is required. Under these circumstances, a spotting method that applies inkjet technology has been proposed as a method for solving the first problem and the second problem among these problems of the above-described DNA chip manufacturing method ( (For example, JP-A-11-187900).

An object of the present invention is a liquid ejection device suitable for efficient production of sample carriers such as probe carriers such as probe arrays and having a simple structure, and a sample carrier production device and production method using the same. To provide.

[0012]

In view of the above-mentioned problems in the prior art, the present invention aims to solve the problems by proposing a liquid ejecting apparatus having the following structure.

A liquid ejecting apparatus according to the present invention is a liquid ejecting apparatus having an ejection port for ejecting a liquid, a pressure chamber, pressure control means for changing the atmospheric pressure in the pressure chamber, the pressure chamber and the ejection port. And a discharge energy generating element that applies an energy for discharging the liquid in the flow path from the discharge port to the liquid, and the pressure control means reduces the pressure in the pressure chamber. In the state
A liquid ejecting apparatus, characterized in that a liquid to be ejected is introduced from the ejection port into at least the flow path.

The apparatus is provided with a chamber for holding the liquid in the vicinity of the discharge port in the flow path,
It is preferable to have a configuration in which the energy is applied to the liquid held in the chamber.

The diameter of the discharge port in this device is 10-8.
It is preferably in the range of 0 μm.

Further, the maximum volume capable of holding the liquid in this apparatus is preferably in the range of 1 to 1000 nl.

Further, it is preferable that the inner wall of the opening of the discharge port and the outer wall of the discharge port have water repellency.

Further, as the pressure control means, one that changes the atmospheric pressure in the pressure chamber by heating can be used, and specifically, a heater driven by an electric pulse can be preferably used.

Further, as the pressure control means, a Peltier element driven by an electric pulse can also be used.

Heat energy can be preferably used as the energy used for discharging the liquid, and a heater driven by an electric pulse can be used as the discharge energy generating element.

On the other hand, a sample carrier manufacturing apparatus according to the present invention is a sample carrier manufacturing apparatus in which a sample is carried on a carrier, and comprises a liquid ejecting apparatus having the above-mentioned structure and a pressure control means of the liquid ejecting apparatus. First driving means for driving, second driving means for driving the discharging energy generating means of the liquid discharging apparatus, and liquid for holding the liquid containing the sample discharged from the liquid discharging apparatus Holding means, carrier holding means for holding the carrier, moving means for moving the discharge port of the liquid ejection device relative to the liquid holding means and the carrier holding means, and the liquid Positioning is performed by moving the discharge port relative to the carrier held on the carrier holding means in a state where the liquid to be discharged is introduced into the flow path through the discharge port of the discharge device. Place to do It is a manufacturing apparatus of a sample carrier, characterized in that it comprises a control means.

Further, a method for producing a sample carrier according to the present invention is a method for producing a sample carrier in which a sample is carried on a carrier, and the ejection port of the liquid ejecting apparatus having the above-mentioned structure is brought into contact with the liquid containing the sample. In this state, the step of filling a liquid into the flow path communicating with the discharge port via the discharge port, and the discharge port of the liquid discharge device filled with the liquid in the flow path to the carrier. A step of moving and positioning relative to each other;
And a step of applying the liquid to a predetermined position of the carrier from the positioned ejection port so as to carry the sample on the carrier.

According to the present invention, it is possible to provide a liquid ejecting apparatus capable of efficiently producing a sample carrier in which a sample is carried on a carrier, an apparatus and a method for producing a sample carrier using the liquid ejecting apparatus. For example, according to the device and method of the present invention, it is possible to easily spot a small amount of various liquids with high density and uniform diameter on the carrier without precisely overlapping,
It is possible to provide a highly reliable small liquid ejection device. As the small amount of various liquids, for example, a water-soluble reaction substance typified by a DNA probe dissolved in water can be mentioned, whereby a reaction chip integrated on the surface of a recording object, for example, a DNA chip or the like can be used. It can be easily manufactured.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION The sample carrier in the present invention has a structure in which a sample containing a component involved in a desired reaction is supported on the carrier, and for example, a liquid containing the sample is spotted in a predetermined shape on the carrier. The sample spot is formed on the carrier by applying it to a position and performing post-treatment such as drying treatment if necessary. As the sample, a known substance such as a reagent or an unknown sample to be inspected can be used.

An example of this sample spot is a probe carrier. The probe used for the probe carrier can be specifically recognized by a specific target (target), and is often called a ligand. Further, the probe includes an oligonucleotide or a polynucleotide that can be recognized by a specific target, or another polymer. The term "probe" means a molecule itself having a probe function such as an individual polynucleotide molecule, and a molecule having a same probe function such as a polynucleotide having the same sequence immobilized on a carrier surface in a dispersed state or the like. It may mean a group. In addition, the probe is a ligand
Those capable of binding to, or becoming capable of binding, the target as part of the anti-ligand. Probes and targets can include bases as found in nature, or analogs thereof.

The probe is appropriately selected according to the purpose of use, but it may be DNA, RNA, or cDNA.
(Complementary DNA), PNA, oligonucleotide, polynucleotide, other nucleic acid, oligopeptide, polypeptide, protein, enzyme, substrate for enzyme, substrate for antibody, epitope for antibody, antigen, hormone, hormone receptor, ligand, ligand receptor, Examples thereof include oligosaccharides and polysaccharides. At least one selected from these can be used.

A plurality of types of these probes, each of which is fixed to the surface of the carrier as an independent area, for example, a dot-shaped spot, is called a probe carrier, and those arranged at predetermined intervals are called a probe array. The probe carrier includes a test plate or chip generally called a DNA microarray, a DNA chip, or a probe array.

On the other hand, the probe has a structure capable of binding to the surface of the carrier, and it is desirable that the probe is immobilized on the carrier via this structure capable of binding. At that time, the structure capable of binding to the carrier surface of the probe is an amino group, a sulfhydryl group, a carboxyl group, a hydroxyl group,
Acid halide compound (haloformyl; -COX), halide compound (-X), aziridine, maleimide group, succinimide group, isothiocyanate group, sulfonyl chloride group (-SO ₂ Cl), aldehyde (formyl group; -C
It is preferably formed by a treatment of introducing at least one organic functional group such as HO), hydrazine and iodoacetamide.

Further, the surface of the carrier may be subjected to a required treatment depending on the structure required for binding to the carrier on the probe side.

Hereinafter, the DNA of the embodiments of the present invention will be described.
A method for manufacturing a chip will be described as an example. The solution used for preparing the probe solution may be an aqueous solution of another water-soluble reaction substance as long as it satisfies the conditions generally usable in an inkjet as described below. That is, the liquid agent used in the liquid ejection apparatus of the present invention, which will be described in more detail in Example 1 below, can be ejected as fine liquid droplets by using an inkjet technique.
In addition, any material can be used as long as it satisfies the condition that the reactive substance in the ejected droplet is hardly damaged by the ejection, and more generally, it is a reaction in which various reactive liquid agents are accumulated on the surface. It can be said that it can also function as a chip manufacturing device.

First, in order to be able to eject as liquid droplets, it is preferable that the liquid agent has, for example, a viscosity of 1 to 15 cps and a surface tension of 30 dyn / cm or more. Especially viscosity 1-5cps, surface tension 30-50dyn / c
In the case of the liquid agent of m, the landing position becomes extremely accurate, so that it can be suitably used. Considering the ejection of the liquid agent by inkjet and the stability of the DNA probe during the ejection, for example, 2 me
r ~ 5000mer, especially 2mer ~ 60mer DN
A probe, 0.05-500 μM, especially 2-50
It is preferably contained at a concentration of μM. Next, as the composition of the liquid agent, a liquid composition which does not substantially affect the DNA probe when mixed with the DNA probe and when ejected, and which can be normally ejected is preferable. There is no particular limitation as long as the conditions are satisfied. Liquids containing, for example, glycerin, urea, thiodiglycol or ethylene glycol, isopropyl alcohol, acetylene alcohol are preferred. More specifically, urea is 5 to 10 mass% and glycerin is 5 to 1
A liquid containing 0% by mass, 5 to 10% by mass of thiodiglycol, 0.02 to 5% by mass, and more preferably 0.5 to 1% by mass of acetylene alcohol is preferably used.

Further, in order to fix the spot of the above liquid agent adhering to the surface of the recording object to the surface of the recording object, to prevent contamination with spots close to each other, and to firmly bond the DNA probe to the surface of the recording object. As an effective means, there has been proposed a method in which functional groups capable of reacting with each other are bound to both the DNA probe and the surface of the recording object (JP-A-11-187900), and a liquid agent treated by this method (for example, -SH group) and a recording object (for example, maleimide group bonding) are used to direct the liquid agent by an inkjet technique to a recording object placed at a position close to the discharge port by a predetermined distance of 1 to 2 mm. When ejected, the quality of the spotted liquid agent is negligibly small, and the spot shape of the liquid agent attached to the recording object is almost circular. Even when the inter-axis distance is spotted ultra high density solutions of about 100μm it can be effectively prevented the connection between adjacent spots. After that, the fixing reaction between the liquid agent and the surface of the recording object is promoted by an appropriate method, and after the fixing is completed, the unreacted liquid agent on the recording object is washed off to obtain a reaction chip.

In order to discharge the liquid agent satisfying the above conditions,
The liquid ejecting apparatus according to the present invention will be described below in detail with reference to the drawings, but the present invention is not limited to the following description as long as it is an apparatus using a part of the characteristic functions.

(Embodiment 1) FIG. 1 is a schematic view of a liquid ejecting apparatus according to the present invention, and FIG. 2 is a schematic view of a reaction chip manufacturing system using the liquid ejecting apparatus of the present invention.

The liquid discharging apparatus of the present invention comprises a container having a very simple and characteristic tubular structure. As shown in FIG. 1, one end of the elongated tubular channel is open and the other end of the tubular channel is closed to keep airtightness, that is, a thin long tubular container is It is a basic shape of the liquid ejection apparatus of the present invention. Explaining the basic configuration of the liquid ejecting apparatus, first, the opening of the narrow channel, which is the mouth of the container, functions as an injection port when the solution is taken into the channel from the outside, but at the same time ejects the solution. It also functions as a discharge port. The inner wall of the flow path, which is close to the liquid discharge port, has a chamber for holding the solution when the solution is taken into the flow path, and a discharge energy generating means for generating discharge energy on a part of the wall of the chamber ( Hereinafter, a heater as a discharge means) is provided. A pressure chamber and a heater as an example of a pressure control unit (hereinafter, referred to as a pressure increasing / decreasing unit) for changing the air pressure in the flow chamber, that is, for increasing / decreasing the pressure in the pressure chamber are provided in the back of the flow channel. However, in the figure, the electrodes and the like that are exposed to the outside of the liquid ejection device for driving and controlling the ejection means and the heater are omitted.

Next, the structure will be described.

In this embodiment, a heater is used as the pressure increasing / decreasing means. When an electric current is passed through the heater of the pressure increasing / decreasing means, the gas in the pressure chamber is heated and the gas in the pressure chamber expands. When the flow of electricity to the heater is stopped, the heat of the gas in the pressure chamber radiates heat to the outside air, which cools the gas, causing the gas in the pressure chamber to contract (cooling is the easiest way to dissipate heat, but electrically It is difficult to control, so in this case it is possible to arrange a Peltier element etc. near the heater).
The pressure in the flow channel can be increased or decreased by the expansion and contraction of the gas in the pressure chamber. By controlling the pressurizing / depressurizing means in the procedure described in more detail below, it becomes possible to fill the solution in the channel and, conversely, to discard the solution in the channel. Further, the heater, which is a discharging means, is for the purpose of rapidly generating heat by applying an electric pulse to cause a rapid phase change in the solution in contact with the heater. The pressure of the bubbles generated at this time causes the solution inside the flow path to be ejected into extremely small droplets from the ejection port. The amount of solution that can be discharged by such a mechanism includes the area and input energy of the heater that is the discharging means, the area of the discharge port, the cross-sectional area of the flow path,
It can be controlled within a range of 2 to 80 pl depending on the configuration such as the distance between the discharge port and the heater, and it can be seen that it is very effective to use it as a means for spotting the solution at high density. Especially when placing droplets with a center-to-center distance of 100 μm or less, it is necessary to fill the chamber because the amount of droplets discharged at one time is preferably 2 to 8 pl in order to prevent contamination between adjacent spots. The amount of such a solution is also very small. As a result, the diameter of the outlet is 10 to 30μ.
It can be seen that it is sufficient that the volume of the entire flow channel is 1 to 10 nl.

FIG. 2 shows a reaction chip manufacturing system equipped with the liquid discharge device of FIG. The liquid ejection device of FIG. 1 is xy
It is mounted on a carriage that can move precisely in the z direction. In addition to the liquid ejecting device and carriage, and the carriage moving mechanism in the xyz directions, the reaction chip manufacturing apparatus includes a solution reservoir containing a pre-synthesized probe solution, a waste pod for discarding excess solution, and a chip and a chip. The transport mechanism includes a control unit (not shown) that controls the drive of the liquid ejection device, the movement of the carriage, and the transport of the chips in conjunction with each other.

The following is in the reaction chip manufacturing system:
It is a procedure of filling the liquid of the liquid ejection device, ejecting the solution, discarding the solution, and spatially moving the liquid ejection device. For ease of understanding, FIG. 3 shows an operation diagram focusing on the ejection device together with the following operation flow. However, in FIG. 3, the pressure chamber, the chamber, the filling of the solution, and the discharge of the discharge device are shown in a cross-sectional view of the discharge device so that they can be easily understood. (1) The liquid ejecting apparatus is moved to directly above the probe solution reservoir, or the reservoir is moved to just below the liquid ejecting apparatus. (2) The pressure chamber is depressurized by the pressurizing / depressurizing means, and at the same time, a required amount of the probe solution is injected into the chamber of the liquid ejection device from the reservoir through the ejection port of the liquid ejection device. Hereinafter, the method of depressurizing the pressure chamber and the method of taking the probe solution into the chamber in this process will be described in detail. In this embodiment, a heater and a cooler that act on the air in the pressure chamber are used in combination as the pressurizing and depressurizing means. A) Air in the pressure chamber of the liquid ejection device is heated and expanded by a heater provided in the pressure chamber. B) The liquid ejection device or the reservoir is moved up and down so that the ejection port is immersed in the probe solution in the reservoir. C) The air in the pressure chamber is naturally cooled (radiated) or forcedly cooled using a Peltier element or the like to contract. That is, the air in the pressure chamber is depressurized by this temperature change, but D) at the same time, the required amount of the probe solution in the reservoir is taken into the chamber through the discharge port. E) The liquid ejection device or the reservoir is moved up and down so that the ejection port is separated from the probe solution in the reservoir. (3) The liquid ejection device is moved to an ejection position that orients the spot to a predetermined position of the recording object, or the ejection position of the liquid ejection device that orients the recording object to a predetermined position of the recording object. Move up to. (4) By rapidly heating a heater, which is a discharge means arranged on one surface of the inner wall of the chamber, the probe solution is made into fine droplets by the pressure of the bubbles generated by the phase change of the probe solution in contact with the heater. The liquid is ejected from the ejection port, and the microdroplets are landed on a predetermined position of the recording object located at a position facing the ejection port. (5) After the ejection of the probe solution is completed, the liquid ejecting apparatus is moved directly above the probe solution discarding pot, or the probe solution discarding pot is moved directly below the liquid ejecting apparatus. (6) The probe solution remaining in the chamber is discarded in the probe solution discarding pod. As a method of discarding the probe solution, in this embodiment, air in the pressure chamber of the liquid ejection device is expanded by heating a heater provided in the pressure chamber, and the pressure chamber is pressurized. (7) The liquid ejecting apparatus is moved to a position directly above the reservoir for the next different probe solution, or the reservoir is moved to a position directly below the liquid ejecting apparatus. (8) Return to (2) above and repeat the subsequent operations.

In the procedure of the reaction chip manufacturing system of the present embodiment, different probe solutions are filled with one nozzle → discharge → disposal of solution → ..., and the previous solution remains in the channel. And in terms of reliability, it may not be very desirable. Therefore, in order for this system to operate properly, the inner wall and the outer wall of the flow path in the vicinity of the ejection port including the chamber of the liquid ejection device of this embodiment are treated to be water repellent so as to retain water repellency. It is preferable. By keeping the wall surface that is directly in contact with the solution water-repellent, it is possible to almost neglect that the previous solution remains in the flow channel by simply discarding the solution in the flow channel according to this procedure. To obtain 100% reliability, a probe solution reservoir is provided in addition to the probe solution reservoir, and the procedure of the reaction chip manufacturing system is as follows: probe solution filling → discharge → solution discarding → detergent filling → detergent discarding → next Sufficient effect can be obtained by filling with the probe solution of →→. In the reaction chip manufacturing system of the present embodiment, a waste pot is particularly provided when discarding the excess probe solution, but there is a possibility that the change in the components of the probe solution due to ejection is extremely small and the reliability of the system is impaired. In this case, returning the surplus probe solution to the reservoir containing the original probe solution causes no problem and does not impair the effects of the present invention.

(Embodiment 2) In Embodiment 1, a heater driven by an electric pulse from the outside was used as an example of the discharging means and the pressurizing / depressurizing means, but in Embodiment 2, for example, as shown in FIG.
A heater was provided outside the liquid discharge device, and the heat generated from the heater was skillfully transferred to the inside of the flow path so that the heat from the heater could be transferred to the inside of the flow path. It may be formed of a material having high thermal conductivity (eg, silicon, metal, etc.). In order to operate each means, the corresponding external heater is moved in the direction of the arrow in the figure and brought into contact with each means to transfer the heat from the heater to the inside of the flow path. The liquid ejecting apparatus of the second embodiment does not have a complicated circuit inside the flow channel, and thus the flow channel is easier to manufacture than the first embodiment. Therefore, the manufacturing cost of one nozzle is low, and this nozzle may be disposable after discharging at least once. In this case, the water repellent treatment inside the flow channel, which was necessary in the nozzle of Example 1, is not necessary.

In the case of this embodiment, for example, as in the first embodiment,
Solution filling into one flow path → discharge → discarding solution → (washing →) filling next solution → ... without filling the process of filling solution → discharging → discarding nozzle → replacing nozzle →
Follow the process of filling the solution → ...

(Embodiment 3) In Embodiment 3, a plurality of nozzles of Embodiments 1 and 2 are arranged. Increase the efficiency of the manufacturing system by performing the process of filling and discharging the solution with a plurality of nozzles at the same time as described in the description of Examples 1 and 2 or by performing the operation procedure for each nozzle in parallel while shifting several steps. .
FIG. 5 shows an enlarged view of the head portion (assembly of discharge nozzles) of the reaction chip manufacturing machine.

A method for controlling such a plurality of nozzles will be described with an example. Regarding the filling and discharging of the solution in the nozzle, the pressurizing / depressurizing means used for disposal, and the discharge of the solution, if they are, for example, electrically driven heaters, electrical design and mounting may be performed so that they can be matrix driven. In particular, regarding the filling and disposal of the solution in the nozzle, there is a simple and reliable method in which these can be performed all at once rather than electrically controlling the individual liquid ejection devices as described above. For example, in a bundle of liquid ejection devices as shown in FIG. 6 in which solution reservoirs are arranged in a matrix and arranged at the same pitch as that,
The heated silicone rubber is pressed from the direction opposite to the discharge port to expand the air in the pressure chamber of each liquid discharge device, and the bundle of this liquid discharge device is brought into contact with the solution reservoir, and the flow path of each liquid discharge device Fill the solution inside. Dispose of the solution in the same way.

(Embodiment 4) This embodiment is a further development of this system. The liquid ejecting apparatus described in Examples 1 to 3 fills the channel with the solution, ejects ultra-fine droplets once, and discards most of the remaining solution. This is not so preferable because of problems of efficiency, cost, and environmental problems of waste liquid. In order to solve this problem, a method of ejecting the solution filled in the flow path almost without leaving the solution, that is, a method of ejecting droplets a plurality of times by filling the solution once will be described. In order to realize this, a control means for controlling the pressure increasing / decreasing means and the discharging means in cooperation with each other is required. In the method, after filling the flow path with the solution, the liquid ejection device is moved to the ejection position, and the pressure chamber is pressurized by the pressure increasing / decreasing means. If it is left as it is, the filled solution will flow out in a liquid column shape from the ejection port, but this is exactly the same idea as in a continuous type ink jet, and this liquid column can be precisely formed into minute droplets. In order to separate into two, it is necessary to accurately chop the solution flowing out from the discharge port. The chopping method may be performed by driving the liquid ejecting means provided in the liquid ejecting device at an appropriate constant frequency, and a plurality of microdroplets are ejected at this frequency. If the liquid ejection head is moved accurately in consideration of the driving frequency at this time, the solution can be spotted on a plurality of chips by filling the solution once (FIG. 7).

[0046]

According to the present invention, a reaction chip having a reactive substance such as a DNA probe accumulated on its surface can be easily provided.

[Brief description of drawings]

FIG. 1 is a diagram showing an outline of a liquid ejection apparatus (Example 1) of the present invention.

FIG. 2 is a diagram showing an outline of a reaction chip manufacturing apparatus (Example 1).

FIG. 3 is a diagram illustrating the operation of the liquid ejection apparatus (Example 1).

FIG. 4 is a diagram showing an outline of a liquid ejection apparatus (Example 2) of the present invention.

FIG. 5 is an enlarged view of a liquid ejection section of a reaction chip manufacturing apparatus (Example 3).

FIG. 6 is a diagram showing a control method of a multi-nozzle configuration.

FIG. 7 is a diagram showing a discharge control method (Example 4).

FIG. 8 is a front view of a reaction chip.

Claims (14)

[Claims] 1. A liquid ejecting apparatus having an ejection port for ejecting a liquid, comprising: a pressure chamber, pressure control means for changing an atmospheric pressure in the pressure chamber, and a flow path connecting the pressure chamber and the ejection port. A discharge energy generating element that applies energy for discharging the liquid in the flow path from the discharge port to the liquid, for discharging in a state where the pressure chamber is depressurized by the pressure control means. A liquid ejecting apparatus, which introduces liquid from the ejection port into at least the flow path. 2. The liquid ejecting apparatus according to claim 1, wherein a chamber for holding the liquid is provided in the vicinity of the ejection port in the flow path, and the energy is applied to the liquid held in the chamber. . 3. The liquid ejection device according to claim 1, wherein the diameter of the ejection port is in the range of 10 to 80 μm. 4. The maximum volume capable of holding the liquid is 1 to
The liquid ejection device according to claim 1, wherein the liquid ejection device is within a range of 1000 nl. 5. The liquid ejecting apparatus according to claim 1, wherein an inner wall of the opening of the ejection port and an outer wall of the ejection port having water repellency. 6. The liquid ejecting apparatus according to claim 1, wherein the pressure control means changes the atmospheric pressure in the pressure chamber by heating. 7. The liquid ejection apparatus according to claim 6, wherein the pressure control means is a heater driven by an electric pulse. 8. The liquid ejection apparatus according to claim 1, wherein the pressure control means is a Peltier element driven by an electric pulse. 9. The liquid ejection apparatus according to claim 1, wherein the energy is thermal energy. 10. The liquid ejection apparatus according to claim 1, wherein the ejection energy generating element is a heater driven by an electric pulse. 11. A device for manufacturing a sample carrier in which a sample is carried on a carrier, for driving the liquid ejection device according to any one of claims 1 to 10 and a pressure control means of the liquid ejection device. First of
Driving means, second driving means for driving the ejection energy generating means of the liquid ejecting apparatus, liquid holding means for holding the liquid containing the sample to be ejected from the liquid ejecting apparatus, and the carrier A carrier holding means for holding the liquid ejection device, a moving means for moving the ejection port of the liquid ejection device relative to the liquid holding device and the carrier holding device, and an ejection port of the liquid ejection device. Position control means for relatively moving and positioning the discharge port with respect to the carrier held on the carrier holding means in a state where the liquid to be discharged is introduced into the flow path via An apparatus for manufacturing a sample carrier, comprising: 12. The manufacturing apparatus according to claim 11, which has a plurality of the liquid ejection devices. 13. A method of manufacturing a sample carrier in which a sample is carried on a carrier, wherein the ejection port of the liquid ejection device according to claim 1 is in contact with the liquid containing the sample. A step of filling a liquid into a flow path communicating with the discharge port via the discharge port, and a step of filling the liquid in the flow path with the discharge port of the liquid discharge device relative to the carrier. And a step of positioning the sample on the carrier by applying the liquid to the predetermined position of the carrier from the positioned discharge port and positioning the sample on the carrier. Method for producing carrier. 14. The manufacturing method according to claim 13, wherein a plurality of the liquid ejection devices are used.